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Scripps Team Seeks Oral Diabetes Drug, Focuses Search on GLP-1 Receptor

According to the American Diabetes Association, 20.8 million Americans, or 7 percent of the US population, have diabetes. In April 2005, the US Food and Drug Administration approved Amylin‘s Byetta (exenatide), a synthetic glucagon-like peptide 1 receptor analog, for the treatment of Type 2 diabetes mellitus.
Although exenatide is efficacious, it has pharmacokinetic and dosing limitations that if overcome, could add value to the discovery of small molecule, orally available GLP-1 agonists or potentiators.
Philip Lograsso, an associate professor of molecular therapeutics and director of drug discovery at the Scripps Research Institute in Jupiter, Fl., was recently awarded a three-year, $320,235 R01 grant from the NIH to develop a series of high-throughput assays to drive a drug-discovery program for the GLP-1 receptor, which is implicated in Type 2 diabetes.
The assays will include: a primary cAMP screen to detect selective agonists, potentiators, or antagonists of the GLP-1 receptor; a functional high-content assay that is G-protein independent and designed to monitor receptor internalization and distinguishes the pharmacology of small molecules; and a high-content assay to measure primary beta-cell apoptosis.  
What will the grant money be used for?
We will set up basic assays to look at the function of the GLP-1 receptor so that we can hopefully find small-molecule agonists or potentiators of this receptor. Then we’ll look at the function of the beta cell as well to see if we can basically find assays that prevent beta-cell apoptosis or promote beta cell neurogenesis.
Will you be using the money to hire additional staff?
We probably have our staff in place for this project already.
Can you provide some background on this work?
The basic idea is that the GLP-1 receptor is a clinically validated target for the treatment of type 2 diabetes. Biological therapeutics that are basically analogues of GLP-1 have received FDA approval. However, because they are biological, they have dosing delivery issues associated with their use. They have to be injected either daily or weekly, which is not the ideal dosing regimen.
We thought that, given the clinical validation of the target, a small-molecule agonist would be very useful for clinicians and patients. In drug discovery, if you are working on a target that already has clinical validation, that’s half or a third of the battle.
Do you think that your work would have potential for commercialization?
Yes. Down the road, if we are able to find small-molecule agonists for the GLP-1 receptor, they would definitely have commercial potential. Of course, identifying a receptor agonist and turning it into a drug are two different things.
Is this the direction that you think the diabetes drug-discovery market is taking — looking for inhibitors of the GLP-1 receptor?
I’d say that yes, it is, to a large extent. Certainly people are working very hard on the biologicals, such as exenatide and analogues around that, so there is a lot of activity in that area.
If you look at the small-molecule dipeptidyl-peptidase-4 inhibitors, they are essentially targeting GLP-1 as well. With regards to the small-molecule agonists or potentiators of the GLP-1 receptor, I think there is less activity there. This may be a novel niche, although it is not like we are the only ones to ever think of it.
However, it may be a more difficult task, in the sense that it is more difficult to identify a small-molecule inhibitor of a protein-protein interaction. So although there is some uniqueness and novelty there, I think the target is certainly on everyone’s radar screen, and has been pretty well investigated.
What is the next step in this project?
We will develop these assays to where we have them in a robust, reproducible format, so that we can do a screening campaign and medicinal chemistry around a few small-molecule compounds that have been published. We could make analogues of those compounds and see if we can get a reasonable hit for a GLP-1 agonist/potentiator small molecule.    
Once those assays are in place, and we’ve tested a bunch of those compounds, we’ll know what our chances are of developing them further.
If we have some encouraging results, where we have identified some small- molecule leads, we may apply for more money. The NIH has preclinical drug development grant mechanisms, and we may apply for something like that.
Other potential indications exist for GLP-1, and we may look into those as well. But it is still a little early to say!
Is there a timeline for this?

It’s a three-year grant, but hopefully, we’ll accomplish our goals even sooner.

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